Georgia Tech

As they succeed in clearing a viral infection from the body, some virus-hunting T cells begin to stick better to their target cells, researchers from Emory Vaccine Center and Georgia Tech have discovered.

The increased affinity helps the T cells kill their target cells more efficiently, but it depends both on the immune cells’ anatomic location and the phase of the infection.

After the peak of the infection, cells within the red pulp of the spleen or in the blood displayed a higher affinity for their targets than those within the white pulp. However, the white pulp T cells were more likely to become long-lasting memory T cells, critical for vaccines.

“These results provide a better understanding of how memory precursor populations are established and may have important implications for the development of efficacious vaccines,” the scientists write.

In the mouse model the researchers were using, the differences in affinity were only detectable a few days after the non-lethal LCMV viral infection peaks. How the differences were detected illustrates the role of serendipity in science, says senior author Arash Grakoui, PhD.

Typically, the scientists would have taken samples only at the peak (day 7 of the infection) and weeks later, when memory T cells had developed, Grakoui says. In January 2014, the weather intervened during one of these experiments. Snow disrupted transportation in the Atlanta area and prevented postdoctoral fellow Young-Jin Seo, PhD from taking samples from the infected mice until day 11, which is when the differences in affinity were apparent.

Seo and Grakoui collaborated with graduate student Prithiviraj Jothikumar and Cheng Zhu, PhD at Georgia Tech, using a technique Zhu’s laboratory has developed to measure the interactions between T cells and their target cells. Co-author Mehul Suthar, PhD performed gene expression analysis.

Scientists can improve protein-based drugs by reaching into the evolutionary past, a paper published this week in Nature Biotechnology proposes.

As a proof of concept for this approach, the research team from Emory, Children’s Healthcare of Atlanta and Georgia Tech showed how “ancestral sequence reconstruction” or ASR can guide engineering of the blood clotting protein known as factor VIII, which is deficient in the inherited disorder hemophilia A.

Structure of Factor VIII

Other common protein-based drugs include monoclonal antibodies, insulin, human growth hormone and white blood cell stimulating factors given to cancer patients. The authors say that ASR-based engineering could be applied to other recombinant proteins produced outside the human body, as well as gene therapy.

It has been possible to produce human factor VIII in recombinant form since the early 1990s. However, current factor VIII products still have problems: they don’t last long in the blood, they frequently stimulate immune responses in the recipient, and they are difficult and costly to manufacture.

Experimental hematologist and gene therapist Chris Doering, PhD and his colleagues already had some success in addressing these challenges by filling in some of the sequence of human factor VIII with the same protein from pigs.

“We hypothesized that human factor VIII has evolved to be short lived in the blood to reduce the risk of thrombosis,” Doering says. “And we reasoned that by going even farther back in evolutionary history, it should be possible to find more stable, potent relatives.”

Doering is associate professor of pediatrics at Emory University School of Medicine and Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta. The first author of the paper is former Molecular and Systems Pharmacology graduate student Philip Zakas, PhD.

ASR involves reaping the recent harvest of genome sequences from animals as varied as mice, cows, goats, whales, dogs, cats, horses, bats and elephants. Using this information, scientists reconstruct a plausible ancestral sequence for a protein in early mammals. They then tweak the human protein, one amino acid building block at a time, toward the ancestral sequence to see what kinds of effects the changes could have. Read more

If someone living in America and eating a typical diet and leading a sedentary lifestyleÂ lets a few years go by, we can expect plaques of cholesterol and inflammatory cells to build up in his or her arteries. We’re not talking “Super-size Me” here, we’re just talking average American. But then let’s say that same person decides: “OK, I’m going to shape up. I’m going to eat healthierÂ and exercise more.”

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Let’s leave asideÂ whether low-carb or low-fat is best, and let’s say that person succeeds in sticking to his or her declared goals. How “locked in” are the changes in the blood vesselsÂ when someone has healthy or unhealthy blood flow patterns?

Although treating atherosclerosis with theÂ drug decitabine is notÂ a viable option clinically, Jo’s team was able to find severalÂ genes that are silenced by disturbed blood flow and that need DNA methylation to stay shut off. A handful of thoseÂ genes have aÂ common mechanism of regulationÂ and may be good therapeutic targets for drug discovery.

College football players tend to have stiffer arteries than other college students, even before their college athletic careers have started, cardiology researchers have found.

Although football players had lower blood pressure in the pre-season than a control group of undergraduates, stiffer arteries could potentially predict playersâ€™ future high blood pressure, a risk factor for stroke and heart disease later in life.

Researchers studied 50 freshman American-style football players from two Division I programs, Georgia Tech and Harvard, in the pre-season and compared them with 50 healthy Emory undergraduates, who were selected to roughly match their counterparts in age and race. The research is part of a longer ongoing study of cardiovascular health in Georgia Tech college football players.

The results were presented Saturday at the American College of Cardiology meeting in Washington DC, by cardiology research fellow Jonathan Kim, MD. Kim worked with Arshed Quyyumi, MD, director of Emoryâ€™s Clinical Cardiovascular Research Institute, Aaron Baggish, MD, associate director of the Cardiovascular Performance Program at Massachusetts General Hospital, and their colleagues.

â€œItâ€™s remarkable that these vascular differences are apparent in the pre-season, when the players are essentially coming out of high school,â€ says Kim. â€œWe aim to gain additional insight by following their progress during the season.â€

Despite being physically active and capable, more than half of college football players were previously found to develop hypertension by the end of their first season. Professional football players also tend to have higher blood pressure, even though other risk factors such as cholesterol and blood sugar look good, studies have found. Researchers have previously proposed that the intense stop-and-start nature of football as well as the physical demands of competitive participation, such as rapid weight gain, could play roles in making football distinctive in its effects on cardiovascular health.

In the current study, the control undergraduates had higher systolic and diastolic blood pressure than the football players: (football players: 111/63; control: 118/72). However, the football players displayed significantly higher pulse wave velocity, a measure of arterial stiffness (football: 6.5 vs control: 5.7). Pulse wave velocity is measured by noninvasive devices that track the speed of blood flow by calculating differences between arteries in the neck and the leg.

â€œIt is known that in other populations, increased pulse wave velocity precedes the development of hypertension,â€ Kim says. â€œWe plan to test this relationship for football players.â€

The football players were markedly taller and larger than the control group (187 vs 178 centimeters in height, body mass index 29.2 vs 23.7). The football players also reported participating in more hours of weight-training per week than the control group (5.4 vs 2.6).

Gaucher and Ortlund teamed up to “resurrect” ancient versions of the enzyme uricase, in search of an explanation for why humans develop gout. Yong explains:

The substance responsible for the condition [gout] is uric acid, which is normally expelled by our kidneys, via urine. But if thereâ€™s too much uric acid in our blood, it doesnâ€™t dissolve properly and forms large insoluble crystals that build up in our joints. That explains the painful swellings. High levels of uric acid have also been linked to obesity, diabetes, and diseases of the heart, liver and kidneys. Most other mammals donâ€™t have this problem. In their bodies, an enzyme called uricase converts uric acid into other substances that can be more easily excreted.

Uricase is an ancient invention, one thatâ€™s shared by bacteria and animals alike. But for some reason, apes have abandoned it. Our uricase gene has mutations that stop us from making the enzyme at all. Itâ€™s a â€œpseudogeneâ€â€”the biological version of a corrupted computer file. And itâ€™s the reason that our blood contains 3 to 10 times more uric acid than that of other mammals, predisposing us to gout.

“Our role* on the project was to solve the three dimensional structure of this enzyme using X-ray crystallography to figure out how these ancient mutations led to a decline in uricase activity in humans and apes,” Ortlund says. “We were interested in how this enzyme lost function, and for the future, how we can restore function to this enzyme to create a more â€œhuman-likeâ€ (and thus less immunogenic) protein than the current available bacterial or baboon-pig uricase chimeras.”

(There’s even a patent on this ancient uricase as a potential treatment for gout, and a start-up company named General Genomics)

Their paper also explores what advantage humans might have gained from losing functional uricase. The proposal is: by disabling uricase, ancient primates became more efficient at turning fructose, the sugar found in fruit, into fat. Their results provide some support for the “thrifty gene hypothesis:” the idea that humans are evolutionarily adapted to being able to survive an erratic food supply, which is not so great now that people in developed countries have access to lots of food. The authors write:

The loss of uricase may have provided a survival advantage by amplifying the effects of fructose to enhance fat stores, and by the ability of uric acid to stimulate foraging, while also increasing blood pressure in response to salt. Thus, the loss of uricase may represent the first example of a â€œthrifty geneâ€ to explain the current epidemic of obesity and diabetes, except that it is the loss of a gene, and not the acquisition of a new gene, that has increased our susceptibility to these conditions.Â

Governor Nathan Deal was joined by Ambassador Andrew Young, Georgia State Representative Calvin Smyre and Leroy Hood, founder of the Institute of Systems Biology, in formally proclaiming September 1, 2011 Personalized Medicine Awareness Day in the State of Georgia.

â€œThe collaboration within the ACTSI between these three research universities is an important undertaking and an example of how it should be done,â€ remarked Governor Deal as he kicked off the dayâ€™s program.

A visionary in the personalized medicine field, Dr. Hood developed the DNA gene sequencer and synthesizer and the protein synthesizer and sequencer â€“ four instruments that paved the way for the successful mapping of the human genome.

During his keynote address he proposed a revolution in medicine. Â P4 Medicine â€“ Predictive, Preventive, Personalized and Participatory â€“ is a proactive (instead of a reactive) approach to medicine. The paradigm change will drive radical changes in science.

For P4 medicine to succeed, a cross-disciplinary culture with team science and new approaches to educating scientists, as is done through the ACTSI, has to take place. Dr. Hood predicts the human genome will be part of individual medical records in 10 years.

Leroy Hood, MD, PhD

â€œThe vision of P4 medicine is that each patient will be surrounded by a virtual cloud of billions of data points. Advances in science and technology will reduce this enormous data dimensionality to simple hypotheses about human health and disease,â€ says Hood.

â€œThe ultimate outcome is to create individualized patient disease models that are predictive and actionable. The shift to P4 Medicine will also require societal changes.”

Personalized Medicine Awareness Day celebrated the first-of-its-kind personalized medicine study, approved by the Centers for Medicare and Medicaid Services. The study will determine the utility of genetic testing in calculating doses and reducing the incidence of adverse events associated with the initiation of Warfarin therapy. Warfarin is the worldâ€™s leading anti-blood clotting drug.

Researchers hope the study will provide data to demonstrate that individualizing treatment can improve patient safety and reduce healthcare costs, says Dean Sproles, CEO of Iverson Genetics, Inc., which is collaborating in the study with MSM and the ACTSI.

Governor Deal congratulated the ACTSI for leading the landmark Warfarin study with Iverson and is â€œproud that Georgia will be leading the effort.â€

The Warfarin Study is led by ACTSI Senior Co-Principal Investigator Elizabeth Ofili, MD, MPH, director of the Clinical Research Center, chief of cardiology and associate dean for clinical research at MSM, and will engage 50 sites across the country and 7,000 participants. The first participant was recently enrolled at Grady Memorial Hospital.

â€œThis study should help us understand how to use each patientâ€™s genetic information to deliver a safer and more effective dose,â€ says Ofili.

Sproles noted, â€œThe study is evidence of the growing role of genetics in helping doctors to develop optimal individual treatments for their patients.â€

A panel including Emory medical leaders David Stephens,Fred Sanfilippo and Kenneth Brigham discussed and addressed questions like how to communicate â€˜big scienceâ€™ to the individual, how to move genetic testing to medical outcomes and who owns genome data.

â€œPersonalized Medicine is the future,â€ stated Governor Deal. The presence of Governor Deal, Ambassador Young and Representative Smyre is a sign that policymakers are beginning to recognize that personalized medicine is not just a vision for better healthcare; it has the power to improve health and reduce healthcare costs.

Georgia Tech biomedical engineer Steve Potter explained his work harnessing the behavior of neurons grown on a grid of electrodes. The neurons, isolated from rats, produce bursts of electrical signals in various patterns, which can be â€œtunedâ€ by the inputs they receive.

â€œThe cells want to form circuits and wire themselves up,â€ he said.

As for future opportunities, he cited the technique of deep brain stimulation as well as clinical trials in progress, including one testing technology developed by the company Neuropace that monitors the brainâ€™s electrical activity for the purpose of suppressing epileptic seizures. Similar technology is being developed to help control prosthetic limbs and could also promote recovery from brain injury or stroke, he said. Eventually, electrical stimulation that is not modulated according to feedback from the brain will be seen as an overly blunt instrument, even â€œbarbaric,â€ he said.

Mike Kuhar, a neuroscientist at Yerkes National Primate Research Center, introduced the topic of cognitive enhancers or â€œsmart drugs.â€ He described one particular class of proposed cognitive enhancers, called ampakines, which appear to improve functioning on certain tasks without stimulating signals throughout the brain.Â Kuhar questioned whether â€œsmart drugsâ€ pose unique challenges, compared to other types of drugs. From a pharmacology perspective, he said there is less distinction between therapy and enhancement, compared to a perspective imposed by regulators or insurance companies. He described three basic concerns: safety (avoiding toxicity or unacceptable side effects), freedom (lack of coercion from governments or employers) and fairness.

â€œEvery drug has side effects,â€ he said. â€œThere has to be a balance between the benefits versus the risks, and regulation plays an important role in that.â€

He identified antidepressants and treatments for attention deficit-hyperactivity disorder or the symptoms of Alzheimerâ€™s disease as already raising similar issues. The FDA has designated mild cognitive impairment associated with aging as an open area for pharmaceutical development, he noted.

James Hughes, a sociologist from Trinity College and executive director of the Institute for Ethics and Emerging Technologies, welcomed new technologies that he said could not only treat disease, but also enhance human capabilities and address social challenges such as criminal rehabilitation. However, he did identify potential â€œUlysses problemsâ€, where users of new technologies would need to exercise control and judgment.

In contrast, historian and Judaic scholar Hava Tirosh-Samuelson, from Arizona State University, decried an â€œoverly mechanistic and not culturally-based understanding of what it means to be human.â€ She described transhumanism as a utopian extension of 19th century utilitarianism as expounded by thinkers such as Jeremy Bentham.

â€œIs the brain simply a computational machine?â€ she asked.

The use of military metaphors â€“ such as â€œthe war on cancerâ€ â€“ in the context of mental illness creates the false impression that everything is correctable or even perfectable, she said.

Emory Healthcare is a key player in plans to bring the worldâ€™s most advanced radiation treatment for cancer patients to Georgia.Â Emory Healthcare has signed a letter of intent with Advanced Particle Therapy, LLC, of Minden, Nevada, opening the door to a final exploratory phase for development of The Georgia Proton Treatment Center – Georgiaâ€™s first proton therapy facility.

For certain cancers, proton therapy offers a more precise and aggressive approach to destroying cancerous and non-cancerous tumors, as compared to conventional X-ray radiation. Proton therapy involves the use of a controlled beam of protons to target tumors with precision unavailable in other radiation therapies. According to The National Association for Proton Therapy, the precise delivery of proton energy may limit damage to healthy surrounding tissue, potentially resulting in lower side effects to the patient. This precision also allows for a more effective dose of radiation to be used.

Proton therapy is frequently used in the care of children diagnosed with cancer, as well as in adults who have small, well-defined tumors in organs such as the prostate, brain, head, neck, bladder, lungs, or the spine.Â And research is continuing into its efficacy in other cancers.

The gantry, or supporting structure, of a proton therapy machine.

The closest proton therapy facility to Georgia is the University of Florida Proton Therapy Institute in Jacksonville.Â Currently there are only nine proton therapy centers in the United States, including centers at Massachusetts General Hospital, MD Anderson Cancer Center in Houston and the University of Pennsylvania.

This is an exciting development in our ability to offer not only patients throughout Georgia and the Southeast the widest possible array of treatment options but patients from around the world who can come to Atlanta via the world’s busiest airport, Hartsfield-Jackson International. In addition, we will work to expand its utility and access for patients through collaborative research projects with Georgia Tech and other institutions. Winship physicians will also be able to reach out to their international colleagues and provide direction in how best to study and implement this technology in the care of cancer patients.

Under the letter of intent, Emory Healthcare faculty and staff will provide physician services, medical direction, and other administrative services to the center. Advanced Particle Therapy, through a Special Purpose Company, Georgia Proton Treatment Center, LLC, (GPTC) will design, build, equip and own the center.Â The facility, which will be funded by GPTC, will be approximately 100,000 square feet and is expected to cost approximately $200 million.Â Site selection for the facility is underway, and pending various approvals, groundbreaking is expected in the Spring of 2012.

Congratulations to the winners of the InVenture innovation competition at Georgia Tech. The competition aired Wednesday night on Georgia Public Broadcasting. The winners get cash prizes, a free patent filing and commercialization service through Georgia Tech’s Office of Technology Transfer.

Several of the teams have Emory connections, through the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory, and the Atlanta Clinical & Translational Science Institute.

Emergency medical professionals know that intubation can be rough. The second place ($10,000)Â MAID team created a “magnetic assisted intubation device” that helps them place a breathing tube into the trachea in a smoother way. The MAID was designed by Alex Cooper, Shawna Hagen, William Thompson and Elizabeth Flanagan, all biomedical engineering majors. Their clinical advisor was Brian Morse, MD, previously a trauma fellow and now an Emory School of Medicine surgical critical care resident at Grady Memorial Hospital.

“When I first saw the device that the students had developed, I was blown away,” Morse told the Technique newspaper. “It’s probably going to change the way we look at intubation in the next five to 10 years.”

The AutoRhexis team, which won the People’s Choice award ($5,000), invented a device to perform the most difficult step during cataract removal surgery. It was designed by a team of biomedical and mechanical engineering majors: Chris Giardina, Rebeca Bowden, Jorge Baro, Kanitha Kim, Khaled Kashlan and Shane Saunders. They were advised by Tim Johnson, MD, who was an Emory medical student and is now a resident at Columbus Regional Medical Center.

The finalist Proximer team, advised by Emory surgeon Albert Losken, MD, developed a way to detect plastics in the body, which can help breast cancer survivors undergoing reconstruction.

The ACL is one of the four major ligaments in the knee, somewhat like a rubber band, attached at two points to keep the knee stable. In order to replace a damaged ligament, surgeons create a tunnel in the upper and lower knee bones (femur and tibia), slide the new ACL between those two tunnels and attach it both ends.

Traditional treatment for ACL injuries in children has been a combination of rehabilitation, wearing a brace and staying out of athletics until the child stops growing – usually in the mid-teens – and ACL reconstruction surgery can safely be performed.Â Surgery has not been an option with children for fear of damage to the growth plate that would cause serious problems later on.

Xerogeanes explains that prior to using the 3-D MRI technology, ACL operations were conducted with extensive use of X-Rays in the operating room, and left too much to chance when working around growth plates.

Preparation with the new 3-D MRI technology allows surgery to be completed in less time than the traditional surgery using X-Rays, and with complete confidence that the growth plates in young patients will not be damaged.